CHIP induces ubiquitination and degradation of HMGB1 to regulate glycolysis in ovarian endometriosis

Ovarian endometriosis is a common gynecological condition that can cause infertility in women of childbearing age. However, the pathogenesis is still unknown. We demonstrate that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a negative regulator in the development of endometriosis and reduces HMGB1 expression in endometriotic cells. Meanwhile, CHIP interacts with HMGB1 and promotes its ubiquitinated degradation, thereby inhibiting aerobic glycolysis and the progression of endometriosis. Furthermore, the CHIP agonist YL-109 effectively suppresses the growth of ectopic endometrium in endometriosis mouse model, which could be a potential therapeutic approach for endometriosis. In conclusion, our data suggest that CHIP may inhibit the development of endometriosis by suppressing the HMGB1-related glycolysis. Similar content being viewed by others Data availability Enquiries about data availability should be directed to the authors. Change history 18 March 2023 The missed co-corresponding author has been updated 17 March 2023 A Correction to this paper has been published: https://doi.org/10.1007/s00018-023-04732-9

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We thank Prof. Sun-wei Guo (Fudan University, Shanghai) for generously providing the cell line. Funding This research was supported by the National Natural Science Foundation of China (nos. 81602301 and 81972489), Natural Science Foundation of Shandong Province (no. ZR2021MH235), Shandong Province College Science and Technology Plan Project (no. J17KA254), and Clinical Research Center of Affiliated Hospital of Weifang Medical University (no. 2021wyfylcyj01). Author information Authors and Affiliations Contributions TY, ZY, YS, and QW designed the study; YS, MW, and FS performed the experiments; PQ and AJ reviewed the data and advised the study; CR, ZY, and TY supervised the study; YS and QW wrote the manuscript. Corresponding authors Ethics declarations Conflict of interest The authors declare that there are no conflicts of interest. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. 18_2022_4637_MOESM1_ESM.tif (download TIF ) Supplementary Fig. 1. CHIP suppresses cell proliferation and invasion in vitro. A-B Immunoblot analysis revealed overexpression and knockdown levels of CHIP in EESC cell. Western blot was quantified by Image J software and statistics were normalized to β-actin. C-D Effect of CHIP overexpression or knockdown on the proliferation of EESC cells. E Overexpression of CHIP in EESC cells resulted in a significant decrease of colony formation. Knockdown of CHIP in EESC cells resulted in a significant increase of colony formation. F Overexpression of CHIP in EESC cells resulted in diminished cell invasion. Knockdown of CHIP in EESC cells resulted in enhanced cell invasion. G CHIP overexpression suppressed endometriotic cells migration. CHIP knockdown enhanced endometriotic cells migration. H-I The effects on glucose consumption and lactate production after overexpression or knockdown of CHIP are indicated, respectively. (All data represent mean ± SEM. The Student’s t-test was used for data analysis. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.) (TIF 4192 KB) 18_2022_4637_MOESM2_ESM.tif (download TIF ) Supplementary Fig. 2. Co-localization of CHIP and HMGB1 in cells and tissues. A Representative images of in situ PLA showing the interaction between CHIP and HMGB1 in 11Z cells (scale bar, 20 µm). B Confocal immunofluorescence microscopy was performed to analyze localization of CHIP (red) and HMGB1 (green) in human and mouse ectopic endometrium (scale bar, 20 µm). (TIF 3589 KB) 18_2022_4637_MOESM3_ESM.tif (download TIF ) Supplementary Fig. 3. CHIP decreases the protein level of HMGB1. A-B 11Z or EESC cells were treated with YL-109 (10μmo/L). Immunoblotting experiments were performed. C 11Z cells with overexpression of Flag-CHIP were treated with CHX for indicated time. Immunoblotting experiments were performed. D 11Z cells with knockdown of CHIP were treated with CHX for indicated time. Immunoblotting experiments were performed. (Representative western blot was quantified by Image J software and statistics were normalized to β-actin. All data represent mean ± SEM. Statistical significance was analyzed with Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.) (TIF 1174 KB) Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Sun, Y., Wang, Q., Wang, M. et al. CHIP induces ubiquitination and degradation of HMGB1 to regulate glycolysis in ovarian endometriosis. Cell. Mol. Life Sci. 80, 13 (2023). https://doi.org/10.1007/s00018-022-04637-z Received: Revised: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s00018-022-04637-z